Scoping review of hearing loss attributed to congenital syphilis

Background There are no narrative or systematic reviews of hearing loss in patients with congenital syphilis. Objectives The aim of this study was to perform a scoping review to determine what is known about the incidence, characteristics, prognosis, and therapy of hearing loss in children or adults with presumed congenital syphilis. Eligibility criteria PROSPERO, OVID Medline, OVID EMBASE, Cochrane Library (CDSR and Central), Proquest Dissertations and Theses Global, and SCOPUS were searched from inception to March 31, 2023. Articles were included if patients with hearing loss were screened for CS, ii) patients with CS were screened for hearing loss, iii) they were case reports or case series that describe the characteristics of hearing loss, or iv) an intervention for hearing loss attributed to CS was studied. Sources of evidence Thirty-six articles met the inclusion criteria. Results Five studies reported an incidence of CS in 0.3% to 8% of children with hearing loss, but all had a high risk of bias. Seven reported that 0 to 19% of children with CS had hearing loss, but the only one with a control group showed comparable rates in cases and controls. There were 18 case reports/ case series (one of which also reported screening children with hearing loss for CS), reporting that the onset of hearing loss was usually first recognized during adolescence or adulthood. The 7 intervention studies were all uncontrolled and published in 1983 or earlier and reported variable results following treatment with penicillin, prednisone, and/or ACTH. Conclusions The current literature is not informative with regard to the incidence, characteristics, prognosis, and therapy of hearing loss in children or adults with presumed congenital syphilis.


Introduction
Syphilis is a sexually transmitted infection caused by the bacterium Treponema pallidum.If not recognized and treated early in pregnancy, fetal transmission commonly occurs [1].According to the international Joint Committee on Infant Hearing, congenital syphilis (CS) is a risk indicator for hearing loss [2,3].The Centers for Disease Control and Prevention state: "Otosyphilis is caused by an infection of the cochleovestibular system with T. pallidum and typically presents with sensorineural hearing loss, tinnitus, or vertigo.Hearing loss can be unilateral or bilateral, have a sudden onset, and progress rapidly."(Neurosyphilis, Ocular Syphilis, and Otosyphilis (cdc.gov)).Almost all cases of CS are treated with penicillin which is not known to be ototoxic.
For decades, congenital syphilis had almost disappeared in Canada and the United States due to low rates of syphilis in the community and universal prenatal screening..The number of cases of confirmed early congenital syphilis born to women aged 15-39 years in Canada rose from 17 cases in 2018 to 117 in 2022 [4].Trends in the United States (US) mirror this with an increase from 1325 congenital syphilis cases in 2018 to 3755 in 2022 [5].
The recent resurgence has increased interest in the clinical manifestations and complications of congenital syphilis.There are no published data summarizing the incidence or characteristics of hearing loss due to congenital syphilis.Despite the larger number of cases now occurring in Canada and the US, there are no evidence-based guidelines on screening or management of hearing loss in children with congenital syphilis.We therefore performed a scoping review.Our specific questions were: • How often is hearing loss due to congenital syphilis?
• What is the incidence of hearing loss in children with congenital syphilis?
• When hearing loss occurs from congenital syphilis, what is the usual age of onset?Is it unilateral or bilateral?How severe is it?How rapidly does it progress?
• Is there evidence for any interventions for treatment of hearing loss attributed to congenital syphilis?
This will inform the studies that need to be done to determine the incidence and age of onset of hearing loss from CS, the severity of hearing loss, and interventions that warrant further study.

Methods
The methodology was based on the Preferred Reporting Items for a Systematic Review and Meta-analysis Extension for Scoping Reviews: The PRISMA-ScR statement [6] (See attached S1 Checklist).A search was executed by a health librarian on the following databases: PROSPERO, OVID Medline, OVID EMBASE, Cochrane Library (CDSR and Central), Proquest Dissertations and Theses Global, and SCOPUS using controlled vocabulary (e.g.: MeSH, Emtree, etc.) and selecting key words representing the concepts "congenital syphilis" or "hearing loss" (S1 Appendix).Databases were searched from inception to October 17, 2021, with an updated search to March 31, 2023.Articles were included if they described persons of any age with hearing loss that the authors of the article attributed to congenital syphilis.To delineate the burden and incidence of hearing loss from congenital syphilis, we included any studies that i) screened children with hearing loss for evidence of congenital syphilis or ii) screened children with congenital syphilis for hearing loss.We also included randomized controlled trials (RCTs), cross-sectional studies, case series, and case reports that described the characteristics of hearing loss, the long-term outcomes of hearing loss, or the results of any interventions for hearing loss.We excluded autopsy reports, animal studies, studies focusing solely on acquired syphilis and those published in a language other than English, French, or Portuguese.
Articles published in English were screened by two reviewers independently [AH, KC], and conflicts were resolved by a senior author [JR, NG].Articles published in French had a single reviewer [FS].There were no articles published in Portuguese.Because of the small number of recent articles, preprints were included.The protocol has not been published.
Studies were divided into four types: i) those that screened patients with hearing loss for congenital syphilis, ii) those that screened patients with congenital syphilis for hearing loss, iii) case reports or case series that describe the characteristics of hearing loss in patients with congenital syphilis, and iv) studies that describe an intervention for hearing loss attributed to congenital syphilis.Data were collected and managed using Research Electronic Data Capture (REDCap) tools [7] hosted at the University of Alberta with the extracted data determined by the study type.Data were entered by a single investigator.The JBI critical appraisal tool was used as appropriate to assess all included studies [8][9][10][11] (S2 Appendix).The critical appraisal and bias risk assessment was completed by a single reviewer [NG], and all studies were rated as high, unclear or low risk of bias.

Results
The search yielded 1983 records of which 832 were duplicates.Screening led to 159 records for full-text review of which 36 met inclusion criteria (Fig 1).The figure outlines the reasons for exclusion of other records.

Screening of patients with hearing loss for congenital syphilis
There were 5 studies where patients with hearing loss were screened for CS.They were published from 1900 to 1990 and all had a high risk of bias (Tables 1 and 2).The incidence of CS ranged from 0.3% to 8% in children attending schools for the hearing impaired and was 2% in children seen at a clinic for the hearing impaired.

Screening of patients with CS for hearing loss
There were 7 studies of which 4 were published from 2016 to 2022 (Table 3).The risk of bias was high for 1, unclear for 3, and low for 3. Hearing loss was reported in 0 to 19% of children with probable or proven CS.One study from the modern era showed an incidence of 6% (22/ 342) (12).However, a small recent study reported no hearing loss for 7 infants treated in utero, a 5% incidence for 37 treated at birth, and a 6% incidence in 49 controls [23].

Case series and case reports of hearing loss attributed to CS
There were 10 case series (one of which was also included in Table 2) (Table 4A) and 8 case reports (Table 4B) of which all but 6 were published prior to 1980.The risk of bias was high for 5 articles, unclear for 3 and low for 10.In these reports, hearing loss was often first noted in adolescence or adulthood with the youngest being 5 years old at diagnosis.Many cases also had interstitial keratitis.Follow-up was too variable to allow determination of the expected  rate of progression of hearing loss.A wide variety of therapies are reported with small numbers of patients and inconsistent results that were often subjective.

Studies with interventions for hearing loss
The 7 studies included a range of 6 to 39 patients with the most recent one being from 1983 (Table 5).All were observational.Most commonly patients were prescribed penicillin with addition of prednisone followed by ACTH if response was poor or transient.Outcomes were often subjective and inconsistent.Risk of bias was unclear for 5 studies and low for 2 studies.

Discussion
The scoping review shows that studies of hearing loss due to congenital syphilis are limited and low quality.All but one study reported as a pre-print [23] are observational studies and only 15 of 36 studies (42%) were at low risk of bias.One cannot determine the incidence or characteristics of hearing loss from congenital syphilis or the efficacy of interventions from this review.It seems unlikely that a systematic review would find further studies that could answer these questions.As expected, there were major variations in the study methodologies employed to diagnose hearing loss.In the early 1900s, investigators used basic tuning fork tests and subjective behavioral responses [24].Studies performed after the year 2000, used full diagnostic tests or Auditory Brainstem Responses (ABR) for neonates [21].
A small percentage of children attending schools for the hearing impaired had evidence of congenital syphilis.However, these data are of limited value without a control group from the same jurisdiction.The percentage of hearing loss that is due to congenital syphilis no doubt varies considerably by country and over time.
It is perhaps unexpected that almost all case reports and case series describe recognition of hearing loss only in adolescence or adulthood.It is possible that hearing loss started years prior but was not recognized, particularly, if the hearing loss was slowly progressive.The major problem with all these reports is that they do not exclude the possibility that the patient had acquired syphilis or had another etiology for their hearing loss.
Clearly, there is paucity of up-to-date literature regarding this important health problem.The majority of articles were published before 1980.The recent surge in congenital syphilis cases in Canada and the United States may lead to further studies.Recent results from neonatal hearing screening programs in low-or middle-income countries where the incidence of congenital syphilis never waned are informative.Besen reported screening 21,434 newborns in Brazil 2017 through 2019 and reported a prevalence of test failure in the Universal Neonatal Hearing Screening Program (UNHS) of 1.6% (95% CI: 1.4; 1.8).This study used Otoacoustic Emission and ABR to identify both cochlear and retrocochlear damage.They report that 1.7% (95% CI: 1.5; 1.8) had congenital syphilis but do not report how many with congenital syphilis had hearing loss [22].In a follow-up report of 34,801 infants screened 2017 through 2021, they report that neonates with congenital syphilis were 2.38 times as likely to fail in the UNHS as those without congenital syphilis [48].However, another small study from Brazil reported as a pre-print examined failed hearing screens at 2 months of life did not find an association between congenital syphilis and failed hearing screens [23].
It is not clear whether there is a treatment for hearing loss due to congenital syphilis.Antibiotics were presumably always given at the time of diagnosis of hearing loss if the patient had not previously been adequately treated.There are no convincing reports that this alone resulted in sustained improved hearing.Uncontrolled studies that included corticosteroids with or without ACTH reported variable response and improvement in hearing was often subjective.
The main limitation of this scoping review is the lack of high-quality studies.

Conclusion
Our scoping review outlines a general map of the trend of publications across the decades and shows that the incidence of hearing loss due to congenital syphilis is completely unknown.It is not clear whether the stage of maternal syphilis or the age at which infants are treated changes outcomes.The literature does not inform us as to whether treatment in-utero prevents development of hearing loss.Until there are high quality long-term observational studies, it is difficult to know what hearing screening to recommend for children with congenital syphilis.Hearing loss attributed to congenital syphilis is often first recognized in adolescence or adulthood.Therefore, there is a need to increase awareness that people of all ages with unexplained hearing loss of sudden or gradual onset should be screened for syphilis.Other than treatment of the congenital syphilis, no other treatments can be recommended until there are RCTs or cohort studies with valid control groups.

Table 1 . Critical appraisal of studies of hearing loss attributed to congenital syphilis. Type of study Author (Year) Country Risk of bias Comments
• Study subjects and setting described • ABR used for auditory screening.Note that equipment was changed during study but no statistical significance.•Sufficient data and statistical analysis • Identification of condition valid Case series Yearsley [13] (1910) UK High • Only the demographics and phenotypes of patients in case reports were described.•Method of diagnosis of CS or HL not described • Inclusion or exclusion criteria unclear • Longitudinal reporting and follow up not defined High • No patient's demographics, patient's history, clinical condition, or invention described • only the diagnostic tests or assessment methods in addition to intervention and post intervention clinical conditions • Adverse effects and objectives not clear.(Continued)

Table 2 . Studies where multiple children with hearing loss were screened for congenital syphilis. Author (Year) Country Description of participants screened for CS Number of children with CS
https://doi.org/10.1371/journal.pone.0302452.t002

Table 4 .
A -Case series of hearing loss attributed to congenital syphilis.B -Case reports of hearing loss attributed to congenital syphilis.

Table 5 . Studies with an intervention for hearing loss that was attributed to congenital syphilis with minimal details on individual patients.
ACTH -Adrenocorticotropic hormone; HL-Hearing loss; PTA-pure tone average; SRT-speech recognition threshold.https://doi.org/10.1371/journal.pone.0302452.t005